Summary

Background

Some studies in animals have suggested an anti-atherogenic effect of calcium channel blockers. This study was designed to test the hypothesis in humans. Hypertensive patients were randomized to treatment with hydrochlorothiazide or isradipine, a dihydropyridine calcium antagonist (DynaCirc ®, Sandoz). B-mode ultrasound measurement of the carotid artery intimal-medial thickness was used as an index of atherosclerosis progression.

Methods

Subjects: Patients were recruited in 9 university based clinical centers and were eligible if they were over age 40 with sustained diastolic hypertension after three clinic visits and completion of a 3 to 8 week placebo run-in period (average DBP 90-115 mmHg). Exclusion criteria included hypercholesterolemia (LDL > 160 mg/dL), hyperglycemia, abnormal liver or kidney functions, recent vascular events, history of carotid endarterectomy. On ultrasound examination of the carotids (see below) at least one segment had to have an abnormal IMT measurement (1.3-3.5 mm), in the absence of hemorrhage or calcification.

Of 18,800 potential candidates, 883 met all criteria and were randomized. Overall, 8% were over age 70, 78% were male, 72% white, 41% had never smoked. Mean BP was 150/97, 24% had never been treated previously. Mean LDL cholesterol was 146, HDL was 48.

Treatment: Patients were randomized to either hydrochlorothiazide, 12.5 or 25 mg bid, or isradipine, 2.5 or 5 mg bid. Dose was titrated to achieve diastolic BP less than 90 mmHg (95 for those with baseline diastolic over 105). If this was not sufficient therapy, open-label enalapril, 2.5 to 10 mg bid, was added.

Follow-up: Patients were followed for three years, with visits every 2 months the first year and every 3 months thereafter. Visits included physical exam, bloodwork and EKG.

B-mode ultrasound: Ultrasound of both carotid arteries was performed twice at baseline, every six months during the study and twice at the end. Details of the ultrasound measurements that were performed are given in the article. The intimal-medial thickness (distance between the intima-lumen interface and the media-adventitia interface) was measured at three levels (distal common carotid, carotid bifurcation and proximal internal carotid) on both sides (total of six arterial segments). At each segment, this thickness was measured twice (the near and far walls of the artery) for a total of 12 focal points. At each focal point, several measurements were made and the maximum was taken. The mean of these 12 maximum measurements was calculated and called the mean maximum IMT.

Endpoints: The primary endpoint was a comparison between the rate of progression of the mean maximum IMT in the two treatment groups. Secondary endpoints were the rate of progression in various arterial segments (normal arteries, diseased arteries, common carotid, etc.).

Clinical events: Clinical events that were recorded and analyzed included:

Major vascular events (limited to one recorded per patient): cardiovascular death, stroke, MI, CHF, angina.

Statistics: It was assumed that, in the HCTZ group, IMT would progress in a linear fashion at a rate of 0.15 - 0.20 mm/year, and that treatment with isradipine would slow this by 30-40%. Based on a power to detect such a difference of 90% and a P value of 0.05, the sample size needed was estimated at 800. For the secondary endpoint analyses, a P value of 0.00625 was required because of multiple comparisons.

Results

IMT: The progression of IMT turned out not to be strictly linear in either group, so a model was constructed that yielded two parameters: one parameter reflecting the rate of progression of IMT (termed the "drug x time effect"; in a linear model this would be the slope), and one parameter looking at the overall, mean change from baseline IMT, reflecting the net increase in IMT over the course of the study (termed the "drug effect"; in a linear model, this would be proportional to the area under the curve). These two parameters were then compared for the two study drugs.

At time zero the mean maximal IMT's were equivalent in the two groups; at t=6 months (first ultrasound after baseline) there was an increase in mean maximal IMT for the HCTZ group versus isradipine; thereafter the two curves remained parallel.

As a result, there was no statistically significant difference in the drug x time effect (p=0.68), since the rate of progression of the mean maximal IMT was the same in the two groups except for the first six months. Although the "drug effect" did demonstrate a greater mean maximal IMT for HCTZ vs. isradipine (p=0.02), this was due to the effect seen at 6 months which did not increase thereafter and was not felt to represent a clinically significant effect. By and large, the same considerations held for the secondary endpoints (various individual arterial segments).

In summary, isradipine compared with hydrochlorothiazide did not significantly slow the rate of progression of the intima-media thickening in the carotid arteries.

Blood pressure control: Systolic BP was slightly lower in the HCTZ group (19.5 mmHg lower than baseline, vs. 16 mm Hg for isradipine). Diastolic BP was lowered by 13 mmHg in both groups. About one half of the patients remained on the assigned monotherapy; about one quarter required the addition of enalapril.

Editorial

In an accompanying editorial, Aram Chobanian, MD (Boston University School of Medicine) notes that several design problems may have contributed to the failure of MIDAS to detect any effect of isradipine on the rate of progression of carotid atherosclerosis. The sample size was based on the rate of progression of IMT in a different population (patients with hypercholesterolemia, who were excluded in this trial); enalapril was added to a quarter of patients in both groups; systolic BP was better controlled in the HCTZ group; problems with ultrasound interpretation required a post-hoc correction.

As for the increase in vascular events, in particular angina, Dr. Chobanian notes that a similar effect has been suggested in other studies which have looked at the use of calcium channel blockers for the treatment of coronary disease. Some evidence points to an adverse effect of short-acting dihydropyridines only, some to an effect of all calcium channel blockers. Much of this data is case-control and thus inconclusive, and MIDAS was not designed to look at these issues specifically. Nevertheless, the results do contribute to the evidence that caution should be exercised when prescribing calcium channel blockers, that the long-acting and non-dihydropyridines should be considered preferentially and that first-line therapy for hypertension should probably include other types of agents.

Comment

A digression on the topic of endpoints

This study illustrates the concepts of primary and secondary endpoints (and other measurements). When a study result is significant with a p-value of 0.05, there is a 5% probability that it could be due to chance alone. The more results that are obtained, the higher the likelihood that at least one of them will be due to chance. For example, with 14 comparisons, the probability is better than 50% that one of them will attain a significance of p<0.05 due to chance alone. One way to counteract this problem is to demand a higher level of significance (such as p<0.01) whenever multiple comparisons are made. The problem with this approach is that it reduces the likelihood that a true difference will be uncovered, unless the sample size is increased. Thus, the number of parameters that can be investigated by a study is limited by the sample size. Careful consideration must be given to deciding on the study's endpoints.

The primary endpoint(s) is the main hypothesis the study is designed to look at. In general, the sample size will be determined such that the study will have adequate power to confirm or exclude this primary endpoint (to a given statistical confidence level). In the paper reviewed here, the primary endpoint was the rate of increase in IMT over three years. The sample size was determined such that there would be a 90% probability of uncovering a 30 to 40% decrease in this rate (at a p-value of 0.05).

Secondary endpoints are other aspects that are being investigated. Since multiple secondary endpoints are often specified, a higher level of significance is sometimes required. For this reason, and because secondary endpoints frequently involve subgroup analyses, a positive result remains significant but a negative one does not exclude a true difference (i.e. the study will usually not have adequate power to rule out a true difference as far as the secondary endpoints are concerned).

Finally, any other data that is gathered and compared which is neither a primary nor a secondary endpoint must be viewed with much caution. The risk of coming up with "statistically significant" results due to chance alone increases with the amount of data gathered. Anything that turns up with post-hoc analysis should be viewed as tentative and subject to confirmation by other studies.

In the paper presented here, the increase in vascular events was neither a primary, nor a secondary endpoint; as a result, it needs to be investigated further by other studies. However, this result did not occur in a vacuum -- previous case-control investigations have suggested a similar problem with some calcium channel blockers. This, in turn, reduces the probability that we are dealing with merely a statistical fluke and lends credence to its validity as a problem. As should be apparent from the above considerations, the possibilities of using statistics to back up a pro- or contra- calcium channel blocker position are practically endless. What is needed are more studies (some in progress) and prudent, common sense.

September 15, 1996

Reader comments

Date: Wed, 18 Sep 1996
From: "Gilbert W. Gleim" <gleim@nismat.org>

I would like to point out a few things about the MIDAS study.

1. The group assigned to isradipine had about 5 times more angina
at baseline, according to table 1 of the article. That was
significant at P=.10 (for those readers who don't know the meaning
of a Z score), a strong trend. Under "major vascular events" at
the end of the study, angina was the only event found to be
statistically higher in the isradipine group. It was approximately
3.5 times higher at this point. Obviously, close inspection of table
4 reveals that the only reason "major vascular events" were greater
in the isradipine group is due to inclusion of angina as a "major
vascular event".

2. The study was not powered to find the difference in rate of
progression of IMT observed. The study was designed around
a rate of progression of .15 to .22 mm/year in the diuretic group.
In fact, the diuretic group did not attain that degree of change over
the course of 3 years. This means that a larger sample size would
have been necessary. It should reiterated that
the isradipine group had less total progression than the
hydrochlorothiazide group over the course of three years,
.121 v .149 respectively, P=.02. It seems to have worked.

I would urge all of your readers to view the authors' conclusions of
this study with a great deal of skepticism.

The baseline difference in "history of angina" between the two groups, which you point out, is very important. It certainly could have accounted for a difference in hospitalizations for angina.

Given the slower than predicted rate of progression of IMT, the study was, in fact, underpowered (also noted by Dr. Chobanian in his editorial).

The significance of a lower "total progression", in the absence of a lower "rate of progression" remains unclear to me. The authors seem to suggest that it might be an artefact of ultrasound measurement somehow related to a differential change in artery lumen diameter. This may or may not be the case. The fact that the curves differed at 6 months and then remained parallel does not suggest to me that isradipine had a major, sustained effect on atherosclerosis although, again, the study turned out to be underpowered. -- mj